Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway

Biologics : Targets & Therapy
Yong-Hong PanYong He

Abstract

Although EGFR tyrosine kinase inhibitors (TKIs) have shown dramatic effects against sensitizing EGFR mutations in non-small cell lung cancer (NSCLC), ~20%-30% of NSCLC patients with EGFR-sensitive mutation exhibit intrinsic resistance to EGFR-TKIs. The purpose of the current study was to investigate the enhanced antitumor effect of metformin (Met), a biguanide drug, in combination with gefitinib (Gef) in primary resistant human lung cancer cells and the associated molecular mechanism. H1975 cell line was treated with Met and/or Gef to examine the inhibition of cell growth and potential mechanism of action by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Ki67 incorporation assay, flow cytometry analysis, small interfering RNA technology, Western blot analysis and xenograft implantation. Insulin-like growth factor-1 receptor (IGF-1R) signaling pathway was markedly activated in EGFR-TKI primary resistant H1975 cells as compared to EGFR-TKI acquired resistance cells (PC-9GR, H1650-M3) and EGFR-TKI sensitivity cells (PC-9, HCC827). Inhibition of IGF-1R activity by AG-1024 (a small molecule of IGF-1R inhibitor), as well as downregulation of IGF-1R by siRNA, significantly enhanced the ability of Gef to supp...Continue Reading

Citations

Apr 1, 2020·F1000Research·Steven A Rosenzweig
Dec 16, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Oxana RyabayaEvgenia Stepanova
Mar 7, 2021·Biomolecules·Caterina MancarellaKatia Scotlandi
Mar 27, 2021·Frontiers in Cell and Developmental Biology·Soudeh Ghafouri-FardMohammad Taheri
Nov 14, 2020·Cells·Mario CioceVito Michele Fazio
Sep 11, 2021·Cell Biology International·Larissa J SanchesAlessandra L Cecchini

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Methods Mentioned

BETA
xenograft
flow cytometry
Transfection

Software Mentioned

SPSS
Statistical Package for the Social Sciences ( SPSS )

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